A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240).

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.

Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: a multivariate analysis of risk factors.

We evaluated the courses of 115 consecutive cases of pediatric acute leukemia treated with induction chemotherapy. Seventy-two patients developed fever associated with neutropenia; 15 developed systemic fungal infections. We reviewed multiple demographic and treatment characteristics of these patients in an attempt to identify potential risk factors for the development of invasive fungal disease (IFD). Risk factors identified in a univariate analysis included duration of neutropenia after first fever (P less than .0001), diagnosis of acute nonlymphocytic leukemia (ANLL) (P = .003), onset of fever and neutropenia within 5 days of starting induction chemotherapy (P = .009), and multiple (greater than one) surveillance culture sites positive for fungal organisms (P = .02). In a multiple logistic regression analysis, duration of neutropenia (P less than .001) remained a significant risk factor. The study group of patients had a significantly higher risk of fungal infections than a matched group of leukemia patients developing fever with neutropenia due to postremission consolidation chemotherapy (P = .003). In the first 48 patients, 14 (29%) developed IFD. In the subsequent patients (n = 24), intravenous miconazole (5 mg/kg every 8 hours) was begun at the time of the first fever. One of the 24 patients (4%) given miconazole developed IFD. The use of miconazole was a negative risk factor for the development of IFD in univariate (P = .01) and multivariate (P = .05) analysis. We conclude that pediatric leukemia patients who develop fever associated with neutropenia during induction chemotherapy are at high risk for developing IFD. The role of intravenous miconazole at the time of the first fever in this group deserves further study.

Hemosiderosis in rodents and the effect of acetohydroxamic acid on urinary iron excretion.

Previously reported animal models of hemosiderosis fall short of simulating the human disease state of transfusion-induced hemosiderosis. An explanation for this was found by reexamining heat-treated red blood cell (rbc) loading in the mouse. After 18 intraperitoneal transfusions, each equal to two-thirds of mouse rbc volume, liver Fe reaches a level of 0.3% Fe (dry weight), which is far below the 2%-8% found in heavily transfused patients. Using the easily synthesized chelate compound ferric acetohydroxamate, Fe(AHA)3, liver Fe levels in the rat of up to 2% were achieved after 38 intraperitoneal injections. Fe was distributed in both the reticuloendothelial (RE) system and parenchymal cells, as ascertained by light microscopy. No definite histological or biochemical abnormalities could be demonstrated in loaded rats. Cardiac Fe was approximately doubled. Thus, chelate loading, while producing Fe liver levels similar to those of humans with hemosiderosis, may still be of limited usefulness in studying long-term sequelae. On the other hand, this model can be used in determining responses to chelating agents. To explore this, Fe stores were first labeled by giving 59Fe as 59Fe(AHA)3 prior to loading. In animals loaded to 0.7% liver Fe (calculated), desferroxamine, at a dose of 400 mg/kg, induced a 20-fold rise in urinary Fe. This was duplicated by AHA at a dose of 800-1600 mg/kg. It is concluded that Fe(AHA)3-loaded rats are a potentially useful model of hemosiderosis and that further studies are needed to determine whether AHA can be effective in the treatment of transfusion-induced hemosiderosis.

Clinical pharmacology of high-dose cisplatin.

Although nephrotoxicity has frequently limited conventional treatment with cisplatin to doses of 100-120 mg/m2 per cycle, vigorous chloruresis can permit the administration of high-dose cisplatin (200 mg/m2 per cycle) with minimal nephrotoxicity. Systemic toxicities are worsened, but therapeutic response seems to be enhanced. The pharmacokinetics of cisplatin in plasma and urine were examined to assess the causes of these effects. Plasma disappearance of ultrafiltrable platinum was well-described by a single exponential for each patient. The mean t1/2 was 50% longer for patients receiving high-dose cisplatin than for patients receiving conventional doses. The total systemic exposure was three times greater in the high-dose group, which tends to explain the systemic toxicity and improved tumor efficacy, but not the lack of nephrotoxicity. It is suggested that the kidneys of patients in the high-dose group were relatively protected by dilution of active Pt species in the urine in the tubule lumen as well as by high chloride ion concentrations in the urine.

Adverse reactions to oral cysteamine use in nephropathic cystinosis.

Cysteamine (2-aminoethanethiol) has been given orally to 19 patients with nephropathic cystinosis for periods of 8-24 months in doses ranging from 50 to 70 mg base/kg/day. Adverse reactions were noted in 3 patients early in the study when a rapidly increasing dosage schedule was followed. The reactions included hyperthermia, lethargy and rash. These reactions were not seen when patients were started on a very low dosage which was increased gradually at 3-week intervals to a level which depleted leukocytes of about 90% of their free cystine. All three reactions resolved within 24 h or cessation of therapy and in these cases successful readministration of drug was achieved. Chronic cysteamine administration to pediatric patients with cystinosis is feasible. The efficacy of this therapy is still being evaluated.

Interferon-alpha-2a for the treatment of complex hemangiomas of infancy and childhood.

OBJECTIVE: The authors describe the use of interferon-alpha-2a (IFN-alpha-2a) in the treatment of complex hemangiomas and review the role of interferon (IFN) in this example of an angiogenic disease. SUMMARY BACKGROUND DATA: Hemangiomas are the most frequent tumors of infants and children. They grow rapidly for 6 to 8 months and then resolve over a period of years. Approximately 5% produce life-, sight-, or limb-threatening complications, with mortality rates between 20% and 50%. Aggressive therapy with steroids, arterial ligation or embolization, or surgery has been used in these situations with variable results and high morbidity. Recently, IFN-alpha was found to be effective treatment in these complex hemangiomas. METHODS: Four infants and one child were treated with IFN-alpha-2a at an initial subcutaneous dose of 1 million units/m2/day and a sustained dose of 3 million units/m2/day for 5 to 11 months. Appropriate laboratory values were monitored and adverse reactions and ultimate response to therapy were recorded. RESULTS: Two patients experienced minor complications that were managed easily. Three patients had total or near-total regression of the hemangioma, one had partial (50%) regression, and one had stabilization but no regression after an average of 7.1 months of IFN therapy. CONCLUSION: Interferon-alpha inhibits angiogenesis and endothelial cell migration and proliferation in vitro. The patients in this study add to the growing number who have benefited from IFN therapy. As such, IFN-alpha should be considered as a first-line agent in treating complex hemangiomas of infants and children.

Philadelphia-chromosome positive essential thrombocythemia. Two cases in children.

Two cases of children with essential thrombocythemia (ET) with the presence of a Philadelphia chromosome (Ph1) are presented and discussed. Diagnosis was based on their clinical presentation and marked primary thrombocytosis. The site of the Ph1 translocation, as detected by a 1.2-kb bcr genomic probe, differed in the two patients. These cases, along with other reported cases of Ph1-positive ET in the literature, suggest that the presence of the Ph1 cannot be used to rule out a diagnosis of ET. Additionally, the differing translocation sites in these cases suggests that the exact translocation site may not be significant in determining which cell lineage will predominate in a Ph1-positive myeloproliferative disorder.

High-dose cisplatin in hypertonic saline.

To overcome the dose limiting toxicity of cisplatin we have administered high-dose cisplatin (200 mg/m2 body surface area in five divided daily doses with each dose administered in 250 mL of 3% saline) together with extensive hydration (250 mL/h normal saline with 20 meq KCI/L). In 17 previously untreated patients with poor prognosis nonseminomatous testicular cancer, 8 with tumor-associated obstructive uropathy, there was no statistically significant decrease in creatinine clearance or elevation of serum creatinine after three to four cycles of a high-dose cisplatin in combination chemotherapy regimen. High-dose cisplatin in combination with vinblastine, bleomycin, and VP-16 produced an 88% complete response rate in these high-risk patients who are characterized primarily by the presence of advanced bulky lung and abdominal disease. Six patients with ovarian cancer who had a relapse after treatment with standard dose cisplatin regimens were treated with high-dose cisplatin and three partial responses were seen. Four patients had no adverse effects on renal function whereas 2 patients had transient elevations in serum creatinine (4 to 5 mg/dL). Hypertonic saline did not provide protection against the nonrenal toxicities of cisplatin.

Cisplatin, ara-C and etoposide (PAE) in the treatment of recurrent childhood brain tumors.

Sixteen patients with recurrent childhood brain tumors were treated with intravenous cisplatin, cytosine arabinoside and etoposide (PAE), daily for three days every three to four weeks. Objective responses were observed in 6 of 15 evaluable patients and an additional six patients had stable disease for greater than 6 months. The tumor-specific response rate for astrocytoma/glioma was 3 of 7 and for medulloblastoma was 2 of 4. The mean progression-free interval was 11.0 months and the hazard rate for progression was 0.085 per patient-month of observation. The most common toxicities were neutropenia and thrombocytopenia. Clinically significant ototoxicity was identified in 7 patients. The activity of PAE chemotherapy for recurrent childhood brain tumors warrants further investigation.

Cysteamine therapy for children with nephropathic cystinosis.

We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.